Atherosclerosis is the buildup of plaque in the wall of the arteries leading to a thickening and a reduction in elasticity of the arteries. Atherosclerosis results from injury to the inside layer of the artery. The injury is caused by common activities and diseases such as high cholesterol, high blood pressure, smoking and infection.
Plaques form on the inner walls of the artery at these sites of injury. The plaques are mainly composed of fatty tissue and smooth muscle cells. The formation of plaque often leads to blood clotting due to platelet aggregation at the site of the injury. This clotting may result in a reduction or elimination of blood flow to vital organs, causing heart attacks or other serious conditions. The plaque may also rupture and send a blood clot through the artery, referred to as an embolus, which if deposited in a smaller blood vessel may completely block blood flow.
Antiplatelet activity is desirable in fighting the often fatal results of atherosclerosis. Clopidogrel is an inhibitor of induced platelet aggregation which act by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration.
The chemical name of clopidogrel is methyl (+)-(S)-∝-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate. It has the following structure: 
Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. U.S. Pat. No. 5,576,328 describes a method of preventing the occurrence of a secondary ischemic event by administration of clopidogrel, and is incorporated herein as a reference.
Recent studies have shown that clopidogrel is more effective in blocking platelet aggregation than aspirin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than aspirin even at much lower dosage. A dosage of 75 mg of base equivalent has been shown to be more effective than a dosage of 325 mg of aspirin. In addition to being more effective, clopidogrel produces much less gastrointestinal bleeding than aspirin.
Clopidogrel is administered as its hydrogensulfate (syn. bisulfate) salt. Clopidogrel hydrogensulfate has an empirical formula of C16H16Cl NO2S.H2S04. It is currently being marketed as PLAVIX® tablets, which contain about 98 mg clopidogrel hydrogensulfate, which is the equivalent of 75 mg clopidogrel base. PLAVIX® is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. It dissolves freely in methanol, somewhat in methylene chloride, and poorly in ethyl ether. U.S. Pat. Nos. 4,847,265; 5,132,435; 6,258,961; 6,215,005 and 6,180,793, which are hereby incorporated by reference in their entirety, disclose methods that can be used to prepare clopidogrel hydrogensulfate.
The present invention relates to the solid state physical properties of clopidogrel hydrogensulfate prepared by any of these or other methods. These properties can be influenced by controlling the conditions under which clopidogrel is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account when developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by powder X-ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry.
The discovery of new crystalline forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
U.S. Pat. No. 4,529,596 is directed to the composition of clopidogrel and methods of its use. The 596 patent teaches synthesis of clopidogrel, but fails to suggest or disclose the existence of polymorphs or the amorphous form of clopidogrel. U.S. Pat. No. 4,847,265 is directed to the enantiomer of clopidogrel, and also does not suggest or teach any polymorphs or the amorphous form of clopidogrel. These U.S. patents are incorporated herein by reference.
International Publication No. WO 99/65915 discloses two polymorphs of clopidogrel hydrogensulfate, referred to as Forms I and II, though Form I is originally disclosed in EP 281459.
According to the International Publication No. WO 99/65915, Form I has a PXRD pattern with peaks at 9.2, 10.9, 15.2, 17.9, 18.5, 20.6, 23.0, 23.2, 23.4 and 25.5±0.2 degrees two theta. Form I also has an infrared spectrum with absorption bands at 2987, 1753, 1222, 1175 and 841 cm−1.
WO 99/65915 also discloses clopidogrel hydrogensulfate Form II, according to which has a PXRD pattern with peaks at 12.9, 13.6, 15.6, 17.7, 19.5, 21.6, 23.0, 23.3 and 24.7±0.2 degrees two theta. It has an infrared spectrum with absorption bands at 2551, 1753, 1497, 1189 and 1029 cm−1.
According to Applicants' English translation, in Example 1B, Form I is prepared by dissolving clopidogrel camphorsulfonate in dichloromethane under a nitrogen atmosphere. A solution of potassium carbonate in water is then introduced. The organic phase is then removed, concentrated and added to acetone. The acetone solution is placed in a reactor under nitrogen and a 94% solution of concentrated sulfuric acid is added. The mixture is then distilled and cooled, followed by subsequent crystallization. The crystals are washed and dried to obtain Form I.
According to Chemical Abstract Accession No. 1999:811251, Form II is prepared by addition of a solution of 50 g of clopidogrel camphorsulfonate in 100 mL of dichloromethane to a solution of 9.1 g of potassium carbonate in 70 mL of water. The organic phase was separated, concentrated and dissolved in 229 mL of acetone. The acetone solution was refluxed with 7.4 g of 80% sulfuric acid under nitrogen for 2 h. The solvent was then removed to yield Form II.
Form II may also be prepared from Form I by storing aqueous mother liquor from the crystallization of Form I for 3-6 months.
Four new crystal forms of clopidogrel hydrogensulfate, designated Forms III, IV, V and VI plus the amorphous form of clopidogrel hydrogensulfate, and a novel process for their preparation, and preparation of Form I and II of clopidogrel have now been discovered.